Genomic variants link to hepatitis C racial disparities

// Matthew M. Yeh 1 , Sarag Boukhar 1 , Benjamin Roberts 2 , Nairanjana Dasgupta 3 and Sayed S. Daoud 4 1 Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA 2 The Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, USA 3 Department of Mathematics and Statistics, Washington State University, Pullman, WA 99164, USA 4 Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, USA Correspondence to: Sayed S. Daoud, email: daoud@wsu.edu Keywords: hepatitis C, racial disparity, genomic variants, hepatocellular carcinoma, alternative splicing Received: November 30, 2016      Accepted: July 03, 2017      Published: August 01, 2017 ABSTRACT Chronic liver diseases are one of the major public health issues in United States, and there are substantial racial disparities in liver cancer-related mortality. We previously identified racially distinct alterations in the expression of transcripts and proteins of hepatitis C (HCV)-induced hepatocellular carcinoma (HCC) between Caucasian (CA) and African American (AA) subgroups. Here, we performed a comparative genome-wide analysis of normal vs . HCV+ (cirrhotic state), and normal adjacent tissues (HCCN) vs . HCV+HCC (tumor state) of CA at the gene and alternative splicing levels using Affymetrix Human Transcriptome Array (HTA2.0). Many genes and splice variants were abnormally expressed in HCV+ more than in HCV+HCC state compared with normal tissues. Known biological pathways related to cell cycle regulations were altered in HCV+HCC, whereas acute phase reactants were deregulated in HCV+ state. We confirmed by quantitative RT-PCR that SAA1 , PCNA-AS1 , DAB2 , and IFI30 are differentially deregulated, especially in AA compared with CA samples. Likewise, IHC staining analysis revealed altered expression patterns of SAA1 and HNF4α isoforms in HCV+ liver samples of AA compared with CA. These results demonstrate that several splice variants are primarily deregulated in normal vs . HCV+ stage, which is certainly in line with the recent observations showing that the pre-mRNA splicing machinery may be profoundly remodeled during disease progression, and may, therefore, play a major role in HCV racial disparity. The confirmation that certain genes are deregulated in AA compared to CA tissues also suggests that there is a biological basis for the observed racial disparities.